Reaction products of placenta extracts and penicillin

ABSTRACT

The present invention relates to new penicillin formulations formed by contacting penicillin and pharmaceutically acceptable salt complexes formed from extracts of placenta.

United States Patent Granirer, deceased et al.

[ 1 June 20, 1972 [54] REACTI ON PRODUCTS OF PLACENTA EXTRACTS ANDPENICILLIN [72] Inventors: Louis W. Granirer, deceased, late of BelleHarbor, NY.; by Minna B. Granirer, executor; by Samuel Granirer,executor, both of Belle Harbor, N.Y.; by Robert I. Pearlman, executor,Elizabeth, NJ.

[73] Assignee: Minna B. Granirer, Belle Harbor, NY.

[22] Filed: June 5, 1969 [2| Appl. No.: 830,884

Related US. Application Data [60] Division of Ser. No. 701,465, Nov. 7,1967, Pat. No. 3,5 84,1 17, which is a continuation-in-part of Ser. Nos.ll3,059, May 29, l96l, abandoned, and Ser. No. 299,1 14, July 3 l I964,abandoned.

[52] US. Cl ..424/l05, 424/95, 424/271 [51] lnt.Cl ...A6lk 21/00, A6lk17/00 [58] Field ofSearch ..424/l05,95, 271

[56] References Cited UNITED STATES PATENTS 2,907,695 l0/1959 Adam etal. ..424/95 Primary Examiner-Sam Rosen ArtorneyRobert l. PearlmanABSTRACT II he present invention relates to new penicillin formulations12 Claims, No Drawings REACTION PRODUCTS F PLACENTA EXTRAC'IS ANDPENICILLIN The present application is a divisional application of Ser.No. 701,465, filed Nov. 7, 1967 now U.S. Pat. No. 3,584,117, which inturn is a continuation-in-part of now abandoned applications Ser. Nos.113,059 and 299,114, filed May 29, 1961 and July 31, l964, respectively,all in the name of Louis W. Granirer.

U. S. Pat. No. 2,907,695, issued Oct. 6, 1959, (corresponding toCanadian Pat. No. 655,328) to Elizabeth Adam and Louis W. Granirer,describes a composition derived from placenta and having usefulpharmaceutical properties. The present invention relates to, andrepresents further advancements in, work in the art of said patent.

According to U. 8. Pat. No. 2,907,695, medicinal values are derived fromthe human placenta by contacting the placenta in finely divided formwith an acidic, aqueous alcohol solvent to dissolve from the placenta anextract, and base is added to the solvent containing the extract, toprecipitate the medicinal values herein referred to as placenta-derivedmaterial. This material is useful for relieving the pains and symptomsof rheumatoid arthritis. The structural formula for the placentaderivedmaterial is not known. It is, however, believed to be a magnesiumphosphate complex of crystal structure and analysis as is set forth inthe said patent.

In parent application, U. S. Ser. No. 701,465, a new type ofplacenta-derived material is obtained and the yield of theplacenta-derivable material increased by adding a salt, preferably analkali or alkaline earth metal salt, to the solvent containing placentaextract dissolved therein so that there is obtained a complex of thesalt andingredients of the placenta extract. The complex so derived issimilar in pharmaceutical activity to the placenta-derived material ofsaid patent.

It has now been found that improved pharmaceutical substances can beobtained by reacting the placenta-derived material of said patent and/orthe placenta derived material of the foregoing parent application, withpenicillin. The resulting substance is distinctive in that it retainsthe pharmaceutical effectiveness of the penicillin, while accommodatingthe penicillin for administration to patients who are allergic topenicillin when administered in any of its usual forms. The compositionof the present invention can be used for animal or human therapy.

PROCESS OF RECOVERY ACCORDING TO PARENT APPLICATION In the recovery ofmedicinal values from placenta by contacting the placenta with an acidicsolvent, such as an acidic, aqueous alcohol solution, to provide asolution of an extract of the placenta dissolved in the solvent andleave a portion of the placenta undissolved as placenta residue, theimprovement has been taught of admixing with extract a salt, preferablyinorganic, of an alkali metal or alkaline earth metal, to fonn with theingredients of said extract a pharmaceutically acceptable salt complex.The salt complex has a medicinal value substantially similar to that ofthe magnesium phosphate complex derived by precipitating same from anacidic, aqueous ethanol solution of such extract by the addition ofbase.

The various alkali metal and alkaline earth metal salts, both organicand inorganic, may be employed. Examples thereof are: potassiumchloride, potassium gluconate, potassium tribasic phosphate, potassiumdibasic phosphate, potassium bicarbonate, potassium citrate, potassiumsalicylate, potassium lactate, sodium dibasic phosphate, sodium lactate,sodium salicylate, sodium tribasic phosphate, sodium benzoate, sodiumbicarbonate, sodium chloride, sodium citrate, sodium sulphate, calciumgluconate, calcium lactate, calcium dibasic phosphate, calcium tribasicphosphate, calcium carbonate, calcium citrate, calcium levulinate,calcium mandelate, calcium methionate, calcium chloride, calciumsalicylate, magnesium dibasic phosphate, magnesium tribasic phosphate,magnesium lactate, magnesium carbonate, magnesium citrate, magnesiumsalicylate, magnesium thiosolfate, magnesium trisilicate, strontiumlactate, strontium citrate, strontium carbonate, strontium phosphatetribasic, strontium salicylate.

Magnesium phosphate is especially preferred. The phosphate salts areparticularly desirable. Best results have been obtained with dibasicmagnesium phosphate (Mgl-IPO, 3H2O). With tribasic magnesium phosphatemet-L am. "P Pa enter adm n s a of the medicinal values, someinflammation occurs in the areas of administration. So far as has beendetermined the medicinal values obtained when dibasic magnesiumphosphate is used, is the same in pharmaceutical effect. It is howeverof less potency. On a weight basis, about 60-70, e.g. 65, parts of thedibasic magnesium phosphate complex is equivalent to 15 parts of themagnesium phosphate complex of the said patent, as the complex isdisclosed in FIG. 1 thereof. The pharmaceutical effects observed havebeen the same and the materials, on visual observation, appear to be thesame.

The medicinal values provided by use of the new process are termedpharmaceutically acceptable salt complexes," e.g., those formed byaddition of dibasic magnesium phosphate being called dibasic magnesiumphosphate complexes, this indicating the derivation, or more generallymagnesium phosphate complexes. The latter term is also used togenerically denote the product of said patent, such as the product shownin FIG. 1 thereof, although the materials formed in accordance with thepresent invention are distinct from those formed by the process of U. S.Pat. No. 2,907,695.

In somewhat more detail, the finely divided placenta is contacted with asuitable solvent, which can be acidic, aqueous methyl alcohol or acidic,aqueous ethyl alcohol, or other solvent suitable to yield theplacenta-derived material of said patent. A 75 percent ethyl alcohol, 25percent water mixture can be used, and the acidic condition can beprovided by addition of hydrochloric or sulfuric acid. The initial pHcan be about 2.7. Following the contacting, which can be for about 2hours at 20-30' C., the admixture can be allowed to stand in the cold topermit protein material to precipitate out. A holding period of 4-5hours at 0' C. is recommended. This step of holding in the cold is notessential and can be omitted. After the contacting and holding step, ifany, the solution having the extract dissolved therein is separated fromthe undissolved matter. The salt, e.g., an alkali metal or alkalineearth metal salt, can be added to the separated solution, or,alternatively, precipitation of medicinal values can be effected as isdescribed in said patent and thereafter the inorganic salt can be added.

In the former case, following separation of the solution of extract inthe solvent from undissolved matter, the alkali or alkaline earth metalsalt can be added to the acidic solution, and thereafier a base, such asammonium hydroxide or alkali metal hydroxide can be added to raise thepH to about 9-10, e.g., 9.6. The medicinal values then precipitate.Recovery and working up can be as is described in the aforesaid patent.

ln the alternative procedure, medicinal values as magnesium phosphatecomplex are recovered by adding base to the solution of extract inacidic solvent to precipitate the values, as is described in-saidpatent, and this provides a treated solution which contains extractderived from the placenta as a solute therein, the extract being thatwhich is not precipitated following addition of the base. Alkali oralkaline earth metal salt is then admixed with extract of the treatedsolution, and this provides a salt complex as medicinal values inaddition to that obtained by the addition of base.

Following addition of base to the acidic solution of extract, theprecipitate of magnesium phosphate complex can be separated from thetreated solution, and the treated solution can then be subjected toevaporation to remove the solvent. Extract is deposited from thesolution during the evaporation and this is of a pasty consistency. Theextract can be dissolved in water and the salt can be added to thesolution. Apparently, the salt dissolves and simultaneously the mediumbecomes cloudy, and then the precipitate forms, this being a saltcomplex constituting medicinal values of the placenta. This precipitatecan be separated and worked up as was done in recovery of magnesiumphosphate complex according to said patent. Thus it is to be clearlyunderstood that the phrase mixing of extract of treated placentasolution with salt" encompasses mixing the salt directly with theextract, or first removing solvent to recover the solute-extract andthen adding the salt to a solution prepared from same.

The amount of salt, e.g., as dibasic magnesium phosphate, can be 1l-5,000, preferably 100-3,000, especially 1,000 weight percent of theextract (solute) separated from the treated solution during theevaporation, or equivalent molar amount of other salt. When thefirst-mentioned procedure is employed, i.e., when the salt is added tothe acidic solvent having extract dissolved therein, the amount of saltcan be an amount corresponding to the just mentioned amounts, i.e., theamount which would be used if the other procedure were followed.

ln the practice of the improved method, temperature and pressure are notcritical. The improvement can be realized by merely adding the salt to asuitable medium in which the salt is soluble and the extract isdissolved.

While the placenta used in said patent is human placenta, mammalplacenta in general can be used. Cow placenta has been foundsatisfactory. The cow placenta has been used as a source of themedicinal values and the product derived therefrom is suitable for humantherapy. Good yields are obtained from the cow placenta.

COMBINATIONS WITH PENICILLIN The present invention provides, as novelsubstances, the reaction product of contacting penicillin and a complexof a salt and an acidic, aqueous ethanol soluble placenta extract.

The novel combinations with penicillin can be combinations ofpenicillin, and placenta medicinal values as disclosed by U.S. Pat. No.2.907,695, or placenta medicinal values as derived according to thepreceding description encompassed in the parent application. Whencombined with the materials derived by the procedures of the parentapplication, the dibasic phosphate salt complexes or the tribasicphosphate salt complexes are preferred.

The penicillin can be in any of its usual forms or can be penicillin assuch. Procaine penicillin G is suitable.

The combination with penicillin can be made by contacting penicillinwith a pharmaceutically acceptable salt complex of an extract ofplacenta, such as is described hereinbefore; or in U. S. Pat. No.2,907,695. Both are basically derived by contacting placenta with anacidic solvent and forming a complex therefrom.

The proportion of the components of the combination can be 2 to 30 mg.,preferably to 20 mg., of magnesium phosphate complex according to U.S.Pat. No. 2,907,695 (i.e., of the crystals as shown in FIG. 1 of U.S.Pat. No. 2,907,695), or a corresponding amount of dibasic magnesiumphosphate complex as is produced in Example I, above (i.e., about 4times as much dibasic complex as the complex of said patent), per300,000 units of penicillin. If a salt complex other than the dibasicmagnesium phosphate complex is used, the amount can be the molarequivalent of the amounts mentioned herein for the magnesium phosphatecomplex.

Temperature and pressure are not critical. The medicinal values of theplacenta dissolved in a suitable medium such as an aqueous medium, aremerely added to the penicillin contained in a suitable medium. If thepenicillin is in an aqueous medium as a slurry, upon stirring of theadmixture of the ingredients, the penicillin goes into true solution,indicating that reaction occurs during the contacting.

The combination of placenta values and penicillin can be administeredparenterally, e.g., intramuscularly, to patients sensitive or allergicto penicillin therapy. Upon such use of the combination in clinicaltesting with patients having a history of penicillin allergy, includingallergy to dimethoxyphenyl penicillin, therapeutic responsescharacteristic for penicillin, without any allergic reactions, wererealized.

The dosage in terms of units in penicillin and the frequency ofadministration can be as is the practice for penicillin alone. Anadvantage of the combination, however, is that the new penicillincombination is longer acting than the penicillin used in making thecombination. The combination has been effective within 1 hour afteradministration and effectiveness has continued for 2 3 days.

In particular, the combination has been used effectively, with noallergic reaction, on patients having penicillin allergy history, incases of sore throat, infection of the leg, acute otitis media, severeupper respiratory infection, a leg ulcer, and carbuncle of the neck. Noside effects were observed and there was no indication that thecombination is toxic. Detailed data will be found below.

EXAMPLE 1 Human placenta, in amount of l kilogram, is contacted withaqueous ethyl alcohol (75 percent alcohol) of pH 2.7 at 20-30 C. for 2hours, the resulting material is allowed to stand in the cold, isfiltered, and the filtrate is adjusted to pH 9.6, all as is described inthe example of U.S. Pat. No. 2,907,695. The precipitate which isbelieved to be a magnesium phosphate complex is separated, and thetreated solution, which contains the extract not precipitated uponaddition of base, is subjected to further processing to provideadditional medicinal values.

The treated solutiom is evaporated to dryness on a C. water bath.Solute-extract is deposited from the solution. It is a dark brown,sticky substance, amount to 20 grams. 100 grams of this material isdissolved in 8 oz. of tap water at F. A dark brown solution formsreadily. It is pH 4.5. To this solution, 16 oz. of water and 500 gramsof dibasic magnesium phosphate is added, and the solution is stirredwell at room temperature for about 1 hour. Bubbling which indicatesreaction, occurs. Then, 32 oz. of water at 130 F. are added and another500 grams of dibasic magnesium phosphate is added, and stirring iscontinued for about 1 hour. The resulting solution is then allowed tostand at room temperature for 3 hours. The pH of the solution is then7.0. The solution is then poured into a Pyrex evaporating disk andsubjected to evaporation in an oven at 70 C. for 3 days. The resultingproduct is hard and stone like and of carmel color. This can be groundup with mortar and pestle to provide the medicinal values as a powder.

EXAMPLES 2-13 In each of a series of experiments, 100 grams of the brownsolute-extract prepared in accordance with the process of Example l wasdissolved in 500 cc. '5 of l50 F. water so that the solution was clear.In each case, one'kilogram of one of the alkaline earth metal or alkalimetal salts noted below was then added (10 parts by weight ofsalt/weight part of solute) and thoroughly mixed. The mixture was thenevaporated at a temperature of 55 C. for 3 days to form the medicinallyacceptable salt complex of the present invention. The product was a hardstone-like material which was then ground to a powder with mortar andpestle.

TABLE l Experiment 2 Calcium gluconate To provide the medicinal value ina form suitable for parenteral administration 1 to 3, e.g., 2 grams ofthe foregoing salt complexes can be dissolved in 30 cc. of sterilenormal saline solution (0.9 NaCl), preferably containing as preservative0.5 percent benzyl alcohol and 0.01 percent butaben, by heating amixture of the powder and water on a water bath at 100 C. for 35minutes. Bubbling indicating reaction occurs during this time. Theresulting solution is turbid and of pH 7.0.

EXAMPLE 14 To prepare a penicillin combination according to theinvention, 15 cc. of the saline solution of placenta medicinal valuesmade in Example 1 is admixed with cc. of an aqueous medium containing300,000 units per cc. of procaine penicillin G. After thorough mixingthe material is left standing for 6 hours. Reaction occurs and truesolution forms. The color of the solution is slightly greyish and the pHthereof is 7. This material is suitable for parenteral administration,and is stable at room temperature.

EXAMPLE In a manner similar to that of Example 2, a penicillincombination is made using the product of U.S. Pat. No. 2,907,695 asshown in FIG. 1, thereof. 10 cc. of a normal saline solution containing65 mg. of the placenta medicinal values of U.S. Pat. No. 2,907,695 wereadded to 10 cc. of aqueous procaine penicillin G solution (300,000 unitsper cc.), to provide a case in treating the 35 patients, even afterrepeated injections over a period of 6 to 8 weeks. There was no evidenceof immediate or delayed sensitivity, either of a localized orgeneralized form. It is an accepted medical fact that penicillin allergydoes not disappear spontaneously, and thus these experiments evidencethe advantageous nature of the present invention.

The following illustrates the significant advantages afforded bycombining the placenta-derived material of the present invention withpenicillin in treating penicillin sensitive patients.

EXAMPLE 28 Placenta was contacted with aqueous ethyl alcohol inaccordance with U.S. Pat. No. 2,907,695. Following contact atapproximately room temperature, the admixture was allowed to stand inthe cold to precipitate protein material. Ammonium hydroxide is thenadded to give a pH of 5.4. The admixture is allowed to stand overnightat 0 C. and white'crystals came out of solution. The precipitatedmaterial was removed and the solution having the extract dissolvedtherein subjected to drying so as to recover a brown residue of placentaextract. 100 grams of this brown residue of placenta extract wasdissolved in 1 liter of water at 140 C. l kilogram of magnesiumphosphate (dibasic) was added-to this solution. The materials were thenmixed by stirring. Thereafter they were subjected to evaporation at 70C. in an oven. When dry, the solids were removed from the oven. A 7percent solution of the dry solids was made in normal sterile salinesolution. The 7 percent solution was thereafter resterilized for 35minutes at 100 C. in a enicillin combination accordin to the invention.p g 30 wa ter bath.

EXAMPLES 1647 Procaine penicillin g. in aqueous suspension, and at aconcentration of 300,000 units per cc. was stabilized with 0.2 per- 1.5grams each of the placenta derived salt complexes of cent methyl parabenand 04 percent r l parabem 10 Example were dissolved in 30 Sterilenormal Saline cc.s of the stabilized penicillin solution was admixedwith 15 Solution with the resulting 5 Pereent solution being sterilizedcc. 's of the 7 percent placenta extract solution. The admixture in awater bath. The solution in each case was allowed to cool was h k ll d lft-at room temperature f 3 h to room temperature and mixed with equalparts of procaine Th fter, patients were treated b an intramuscular mipenicillin solution. The admixture was allowed to stand for 3 tion f 2cc 's of a combination solution of penicillin and hours at roomtemperature. placenta extract (referred to as New Penicillin Co.").

The new mixtures were used in the treatment of 35 patients 40 T bl 2sets f th h reviou hi torie of the atients who had a history of severepenicillin sensitivity and were t t d ith re e t to allergy topenicillin treatment and the severely allergic to penicillin therapy.The patie were results afforded by the practice of the presentinvention. As treated by an intramuscular injection of 2 cc. of each ofthe h atie t ith a marked enicillin allergy showed little foregoingmixture of penicillin and placenta extract d rived or no allergy whentreated with the penicillin-placenta extract material. The mixture wasfound to be non-allergic in every of the present application.

TABLE 2 [Case reports on the use of a new penicillin compound] PatientAge Previous History Present History Follow-Up 1. EN. 68 Treated in 1061(May) for pneumonitis with 6 January 1962 developed severe sore throatand follicular Observed at 4week.

penicillin inject. Developed severe urticaria tonsillitis. Temp. 104 F.(Culture revealed Strepto- 8-week,and12- altcr the last injectionlasting two Weeks. coccus hemoyticus.) Received 2 cc. of New Penicillinweek intervals. No Warned never to take penicillin again. 00. Temp.became normal in 12 hours. Unevcntful signs of any local or recovery. Nolocal and no general reaction to the New systemic reaction. PenicillinCo.

2. L.K In 1958 received a series of penicillin injections In 1960developed a severe infection and ulcer of the leg. After 12 weeks withno untoward reactions. The last injec- (Culture showed a Staphylococcusinfection.) She reobservation showed tion left a large localizedswelling. One year ceivcd 2 cc. of the New Penicillin Go. There was nono signs of a delayed later she received another injection of penllocalor constitutional reaction. She received 2 addiallergic reaction.cillin. Within a few minutes she became tional injections on alternatedays without any signs acutely ill; severe swelling of arms, legs, of alocal or general reaction. The infection healed face; shock; fellunconscious to the floor; rapidly. hospitalized; treated with oxygensteroids; adrenalin; ctc. Recovered after 10 days; residual dermatitislasted three weeks.

3. l).K 25 M 1950 received a penicillin injection for an in- October1960 developed a recurrence of the ear infection. No allergic fccted earand developed asevcre skin reac- (Culture revealed a Streptococcushcmolytic orgamanifestations tion. Warned never to take penicillinagain. nism.) lIe received 1 cc. of the New Penicillin Co. No evident at6 weeks.

reaction; no penicillin sensitivity. 2 days later he received a similardose. No local or general reaction. The car ceased to drain; completerecovery.

1. ILT 45 M l!158sev -.rnl penicillin injections with no September 1060carbunclc of neck. Received 2 cc. of the No allergic manifestarenction;August 1050 received 2 cc. procaine penicillin and went into shock;wheezing, cold sweat, convulsions and unconsciousness. Revived in thehospital but had a residual dermatitis for three weeks.

Now Penicillin Co. No signs of any local or general sensitivity.Received a similar dost two days later. No reaction. received a total of4 injections of the New lcncillin Co. with no allergic reaction. Thecarbuuclc hcalcd rapidly.

tions evident at 6 weeks.

TABLE 2 [Case reports on the use of a new penicillin compound] PatientAge Previous lIistory Present History Follow-Up 5. J 15 Unable to takepenicillin in any form. In December 1960 he developed a severe penumoniaof the No signs of any November 1959 took a course of 8 tablets orallyof a penicillin salt and developed a severe rash and fever lasting 7days. In 195!) he had a similar reaction following a penicillininjection.

upper and lower lobes of the left lung which he had for days; temp. 104F. He was given 2 cc. of the New Penicillin Co. and was observed for 1hour. There were no signs of a general or local reaction. Two later thechest was almost clear. He received a similar allergy to the NewPenicillin Co. at any time.

days

dose of the New Penicillin Co. Examination 3 days later; the patient hadmade a. complete recovery. There was no allergic response to the newpenicillin.

G. L.U 39 ILW. October 1961 received an injection of procaine penicillinfor a severe chronic sinusitis and headaches. Within twenty minutes shewas covered from head to foot with giant urticaria. (hives) which lastedfour days.

She was not seen again until December 1961, and was hospitalized; nasalculture revealed a Staphylococcus aureus infection. She received 2 cc.of the New lenicillin Go. There was no local or systemic reaction to theNew lencillin Co. She had a total of four injections No signs of anyallergy to the New Penicillin (lo. at any time.

with no renction at any time. The sinusitis cleared up completely.

The following illustratev that a reaction takes place between theplacenta extract and alkali or alkaline earth metal salt.

a. Whereas triple magnesium phosphate is not soluble in water at roomtemperature up to 140 C., when the placenta extract is added to it, itreadily dissolves with considerable bubbling. These same observationsoccur with other relatively insoluble alkaline earth metal salts.

b. Whereas magnesium phosphate is white, the product obtained byreacting it with placenta extract was yellow and remained so afterrepeated washing.

c. The salt-placenta-extract product is of greater density andcrystallinity than either component alone, and has an aromatic odor notfound in either of the individual components.

The following shows a reaction takes place between the saltplaccntaextract material and penicillin.

a. if the penicillin and salt-placenta extract are admixed and theresultant material rapidly administered, the patient has an allergicreaction. However, if the components are allowed to inter-react, such asby standing for 24 hours, no such allergic reaction takes place uponadministration.

b. When an equal amount of procaine hydrochloride in 25 percent aqueoussolution is added to 1 million units of G powder penicillin dissolved in5 cc. of normal saline solution at room temperature, a fine whiteprecipitate is formed (conventional procaine penicillin effect).However, when cc. of 0.7 percent solution of the product formed byadding magnesium phosphate to the placenta extract was added, thepenicillin precipitate was reduced by one third.

It is noted in passing that the placenta-derived materials when combinedwith various other chemicals oflcr potential in treating variousmaladies. Thus, the brown residue solute extract described in Example 1may be admixed with 25 parts by weight of the following materials, theadmixture when administered in the form of 0.3 gram capsules taken threetimes a day having been found to give improvement in rheumatoidarthritis conditions.

A. Chemicals of the salicylate group, e.g., sodium salicylatc, aspirin(acctyl salicylic acids).

B. The para-aminophcnol type compounds, e.g., acetamilid anducctophcneditin.

C. The pyrazolon derivatives, e.g., aminopyrine.

Additionally, when put into solution the brown residue of Example 1 canbe combined with various sulfonamide drugs, the sulfonamidc drug beingadded to the solution, and then evaporation being effected to obtain adry powder. it has been found that a dose of 0.3 grams every 8 hours hasgiven a good clinical response in patients suffering from rheumatoidarthritis. Typical sulfonamide drugs are: fulfamcrazine, sulfacetamide,sulfadiazinc, sulfamethazine, sulfapyridinc, sulfadimethoxinc.

What is claimed is:

1. The method of producing an active penicillin composition of hightolerance which comprises contacting penicillin with effective amountsof a pharmaccutically acceptable salt complex of an extract of placentadissolved in a solution medium, said complex being selected from thegroup consisting of (a) the salt complex derived by contacting placentawith an acidic aqueous alcoholic solvent to form an acidic extractconantipyrinc and taining active ingredients and precipitated placentacomponcnts and adding to soluble ingredients of said acidic cxtract abase to precipitate said salt complex and leave a soluble portion ofsaid extract, and (b) the salt complex formed by addingto the solubleportion of said extract of (a) afier addition of base a member of thegroup consisting of alkali metal salts and alkaline earth metal salts toform a salt complex thus precipitated from said soluble portion.

2. The process of claim 1 wherein a base is first added to the placentaextract solution to give an alkaline ph and effect precipitation of amedicinal product and provide a treated solution containing extractderived from the placenta, admixing said treated extract containingactive ingredients with av salt of a metal selected from the groupconsisting of alkali and alkaline earth metals, to form a salt complex,whereby a second medicinal product is derived, and contacting penicillinwith said second medicinal product.

3. The method of claim 1, wherein the salt complex is a phosphatecomplex.

4. The method of claim 1 wherein a reactant ratio of 2 to 30 mg of saltcomplex to 300,000 units of penicillin are employcd.

5. The method of claim 2 wherein 10 to 5,000 weight percent of saidmetal salt based on solute not precipitated by said; base is added tosaid treated extract.

6. As a substance, the reaction product fonncd by the process of claim2.

7. The reaction product produced by the method of claim 5.

8. As a substance, the reaction product formed by contacting penicillinwith effective amounts of a pharmaccutically acceptable salt complex ofan extract of placenta dissolved in a solution medium, said complexbeing selected from the group consisting of (a) the salt complex derivedby contacting placenta with an acidic aqueous alcoholic solvent to forman acidic extract containing active ingredients and precipitatedplacenta components and adding to soluble ingredients of said acidicextract a base to precipitate said salt complex and leave a solubleportion of said extract, and (b) the salt complex formed by adding tothe soluble portion of said extract of (a) after addition of base amember of the group consisting of alkali metal salts and alkaline earthmetal salts to form a salt complex thus precipitated from said solubleportion.

9. A substance as in claim 8, wherein the penicillin is procainepenicillin G.

10. A substance as in claim 8, wherein said metal salts are phosphatesalts.

11. The reaction product of claim 8 formed by contacting reactants inthe ratio of at least 2 mg of salt complex to 300,000 units ofpenicillin.

12. A substance, as in claim 8, formed as the reaction product ofcontacting penicillin and a magnesium phosphate complex derived by stepscomprising contacting placenta with an acidic aqueous alcoholic solventto provide a solution of an extract containing active ingredients fromthe placenta dissolved in the solvent and leave a portion of theplacenta undissolved as a placenta residue, and adding base to thesolution of the extract to give an alkaline ph and to precipitate saidmagnesium phosphate complex.

t l 8 l t

2. The process of claim 1 wherein a base is first added to the placentaextract solution to give an alkaline ph and effect precipitation of amedicinal product and provide a treated solution containing extractderived from the placenta, admixing said treated extract containingactive ingredients with a salt of a metal selected from the groupconsisting of alkali and alkaline earth metals, to form a salt complex,whereby a second medicinal product is derived, and contacting penicillinwith said second medicinal product.
 3. The method of claim 1, whereinthe salt complex is a phosphate complex.
 4. The method of claim 1wherein a reactant ratio of 2 to 30 mg of salt complex to 300,000 unitsof penicillin are employed.
 5. The method of claim 2 wherein 10 to 5,000weight percent of said metal salt based on solute not precipitated bysaid base is added to said treated extract.
 6. As a substance, thereaction product formed by the process of claim
 2. 7. The reactionproduct produced by the method of claim
 5. 8. As a substance, thereaction product formed by contacting penicillin with effective amountsof a pharmaceutically acceptable salt complex of an extract of placentadissolved in a solution medium, said complex being selected from thegroup consisting of (a) the salt complex derived by contacting placentawith an acidic aqueous alcoholic solvent to form an acidic extractcontaining active ingredients and precipitated placenta components andadding to soluble ingredients of said acidic extract a base toprecipitate said salt complex and leave a soluble portion of saidextract, and (b) the salt complex formed by adding to the solubleportion of said extract of (a) after addition of base a member of thegroup consisting of alkali metal salts and alkaline earth metal salts toform a salt complex thus precipitated from said soluble portion.
 9. Asubstance as in claim 8, wherein the penicillin is procaine penicillinG.
 10. A substance as in claim 8, wherein said metal salts are phosphatesalts.
 11. The reaction product of claim 8 formed by contactingreactants in the ratio of at least 2 mg of salt complex to 300, 000units of penicillin.
 12. A substance, as in claim 8, formed as thereaction product of contacting penicillin and a magnesium phosphatecomplex derived by steps comprising contacting placenta with an acidicaqueous alcoholic solvent to provide a solution of an extract containingactive ingredients from the placenta dissolved in the solvent and leavea portion of the placenta undissolved as a placenta residue, and addingbase to the solution of the extract to give an alkaline ph and toprecipitate said magnesium phosphate complex.